In order to address the goals for this project, we have used several approaches. First are descriptive studies using the Baltimore Longitudinal Study of Aging (BLSA) and more recently the InChianti Study. The projects focus is on describing the characteristic losses in muscle strength, muscle mass, and physical functioning that occur with aging by examining the entire adult lifespan and their impact on function and longevity. We have previously demonstrated that declining muscle strength and rate of change of muscle strength are independent contributors to mortality in men when considering age, physical activity and muscle mass. We have further shown that muscle power and movement speed are further independent sarcopenic factors that contribute to longevity. In previous work, we have shown that peripheral nerve function has an impact on muscle strength and power that is independent of body size and activity levels. These independent associations of muscle power, movement speed, and peripheral nerve function suggest that nervous system processes are contributing to the importance of sarcopenia on longevity and physical function. To examine the role of the effect of peripheral nerve on physical function across age, we examined the motor unit characteristics (size and firing rate), using surface and intramuscular electromyography in the Baltimore Longitudinal Study of Aging (102 subjects age 22-92 years). Surface-represented motor unit size and firing rate were collected from the vastus medialis during knee extension at 10%, 20%, 30%, and 50% of each subjects maximum isometric voluntary contraction (MVC). Adjusting for differences in MVC, both firing rate and motor unit size per Newton force generated began to increase in the 6th decade of life. Motor unit size increased per Newton force to a greater extent than firing rate in this large muscle. The size of motor units and firing rates used to achieve a given force changes with age, particularly after middle age. Whether these changes precede, follow, or occur concurrent to age-related modifications in muscle structure and contractile properties or sarcopenia is not known. However, the structural and physiological changes in motor unit utilization seem consistent with the decrease in strength, decline in movement speed and response times observed in aging individuals. Alterations in both the peripheral and central nervous systems seem to be major contributors to the sarcopenic process. In related work, we have demonstrated that changes in vibrotactile sensitivity in the feet, which declines with aging, are directly associated with changes in peripheral nerve function. Height and circulating inflammatory markers may influence age-related decline in vibrotactile sensitivity through their negative impacts on peripheral nerve function. Vibrotactile sensitivity is directly related to physical performance as demonstrated in an analysis from the InChianti Study, where we found that in the elderly, poor lower limb vibrotactile sensitivity measured on the plantar surface of the great toe is independently associated with slower self-selected normal gait speed. Thus both sensory and motor components of the peripheral nervous system seem associated with a decline in mobility which subsequently contributes to loss of leg strength and corresponding muscle changes that are major components of the impact of sarcopenia. The impact of sarcopenia on mortality may in part be dependent on homeostatic factors required in the maintenance of neuromuscular function. To explore one aspect of homeostasis, we examined the association between basal metabolic rate and longevity. Basal metabolism is primarily generated by muscle and is directly related to the amount of muscle present and is essential for muscle maintenance. Further, there has been a long term interest in the relationship of differences in species size, metabolism and longevity. We found that basal metabolic rate declined with age at a rate that accelerated at older ages. Participants who died had a higher basal metabolic rates compared to those who survived independent of other well-recognized risk factors for mortality, such as age, body mass index, smoking, white blood cell count, and diabetes. Basal metabolic rate was nonlinearly associated with mortality. Further, a blunted age-related decline in basal metabolic rate was associated with higher mortality, suggesting that such condition reflects poor health status. Working with collaborators at the University of Maryland, we are examining genetic contributions related to muscle hypertrophy and strength. We have identified several genes that contribute to the inherited aspects of how much muscle and strength we have. In previous work, we have reported on relationships between IGF-II, IL6 and ciliary neurotrophic facto (CNTF) and muscle strength and muscle mass. Ciliary neurotrophic factor (CNTF) was of particular interest as it is important for neuronal and muscle development, and we had found an association of CNTF with force production via its influence on motor unit size and firing patterns. The observations suggested that genetic influences on nerve and muscle development impact on how the mature nervous system interacts with muscle, and in movement propagation. In related work, we found that longer androgen receptor repeat in exon 1 in men is associated with higher testosterone blood levels and greater levels of fat free mass. We have examined two genes related to myostatin, a negative regulator of skeletal muscle that plays a key role in muscle development and maintenance, and found that ACVR2B and follistatin loci may contribute to the inter-individual variation in skeletal muscle mass and strength. We also examined the ACTN3 R577X allele of the actinin-3 gene which is an important structural component of the z-disk in type 2 fibers. We found that elite strength athletes showed a lower rate of a nonsense allele than controls suggesting the importance of actinin-3 in muscle strength performance. Recently, we have reported an association between polymorphisms associated TNF alpha and lower muscle mass in men. We are continuing to examine specific gene associations with muscle strength and muscle mass, to improve understanding of the genetic contributions to sarcopenia and mortality. The third area of interest has been the importance of physical activity and exercise on strength and muscle mass changes. We have observed that both being physically active and maintaining higher intensity activity over time is associated with lower mortality in men, but not women. In women, overall activity, including low and moderate levels, are equally important. Thus, perhaps different strategies and activities might be important based on sex. In addition, in the elderly, activity restriction can occur because of fear of falling. We observed that such fears adversely affect physical function and autonomy in the In Chianti population. Thus both psychological and physical factors appear to contribute to fear of falling and the associated restrictions in physical activity. Activity interventions need to consider such issues in designing appropriate physical activities and exercise interventions. We have been interested in alternative strategies for exercise intervention for those less inclined to directly exercise including electromyostimulation and a pedometer as a motivational tool to increase activity.